CTL inhibit viral replication by both cytolytic and non-cytolytic mechanisms, but in most HIV-1-infected persons are ultimately unable to prevent disease progression entirely. Although most studies have examined the lytic potential of CTL, few have addressed the ability of CTL to exert antiviral function in the setting of ongoing viral replication. In addition, the relationship between CTL and CD8-cell mediated non-cytolytic inhibition of viral replication is still not completely understood. During the first two funding periods of this grant, we have developed in vitro systems that allow us to compare the relative inhibitory potential of CTL to control active viral replication, and to determine the factors associated with loss of such control. These studies will focus on well-established and unique cohorts of infected persons, including those treated in the acute stage of infection that go on to control viremia after treatment cessation, and those with class I alleles that are associated with excellent and poor prognosis. Our proposed studies will answer critical questions regarding the role of CTL in HIV infection, including the relative antiviral effect of CTL directed against early vs. late viral proteins; the relationship between protective and non-protective HLA alleles and the ability of CTL restricted through these alleles to inhibit viral replication; and the immunologic changes associated with the loss of control of viremia in vivo. Specifically we propose to: 1) Determine the relative ability ov CTL targeting early and late expressed viral proteins to inhibit viral replication; 2) Determine the role of specific class I alleles associated with progression and non-progression to allow for inhibition of replication and generation of CTL escape; 3) Determine the relationship between viral breakthrough and CTL immune escape in persons who lose control of HIV viremia.